Heterocyclic substituted pyrimidine compounds

ABSTRACT

Novel compounds of the following formula: ##STR1## WHEREIN R&#39; is alkyl of 1 to 3 carbon atoms, X -  is a nontoxic anion; b and c are positive numbers having values such that the positive charge of b moles of cation are neutralized by c moles of anion X -;  and -N  is a bicyclic heterocyclic base, of the group consisting of: ##STR2## wherein the dotted line indicates that the methyl group can be present or a hydrogen group can be present, with the proviso that the two alpha methyl groups are not present at the same time, but that one alpha methyl group is required. These compounds have superior coccidiostatic activity.

This application is a continuation-in-part of co-pending applicationU.S. Ser. No. 459,501 filed Apr. 9, 1974, now abandoned which in turn isa continuation-in-part of co-pending application U.S. Ser. No. 224,620filed Feb. 8, 1972, now abandoned.

This invention relates to novel heterocyclic-substituted pyrimidinecompounds useful in the prevention and cure of coccidiosis. The novelcompounds are effective in controlling coccidiosis when fed inrelatively small amounts to poultry or other animals.

Coccidiosis is a common and widespread poultry disease caused by severalspecies of protozoan parasites of the genus Eimeria, such as E. tenella,E. necatrix, E. acervulina, E. maxima, E. hagani and E. brunetti. E.tenella is the causative agent of a severe and often fatal infection ofthe ceca of chickens which is manifested by extensive hemorrhage,accumulation of blood in the ceca, and the passage of blood in thedroppings. E. necatrix as well as certain other species attack the smallintestine of the chick causing what is known as intestinal coccidiosis.Related species of coccidia such as E. melagridis and E. adenoides arecausative organisms of coccidiosis in turkeys. When left untreated, thesevere forms of coccidiosis lead to poor weight gain, reduced feedefficiency and high mortality in fowl. The elimination or control ofcoccidiosis is, therefore, of paramount importance in thepoultry-raising industry.

It has now been found that certain pyrimidine compounds are highlyactive against the protozoa responsible for coccidiosis, includingprotozoa which are resistant to known coccidiostats. One object of thisinvention is to provide such compounds. Another object is to providesyntheses of such substances. A further object is the provision ofanimal feeds and feed supplements and of water soluble compositionscontaining these pyrimidine compounds. Other objects will be apparentfrom the following discussion of our invention.

According to this invention, it has been found that certain5-methyl(heterocyclic)-2-loweralkyl-4-aminopyrimidine compounds, whereinthe heterocyclic substituent is substituted with at least one methylgroup, are very effective in preventing and treating coccidiosis. Theyare particularly valuable in the cure and control of diseases caused byvarious "resistant" strains of Eimeria. The term "resistant" is one thatis applied to field strains of parasites which do not appear to becontrolled by some commercially available coccidiostats. These parasitesappear identical to known species, yet are presumed variants insofar astheir susceptibility to the commercial coccidiostats is concerned. Thenovel compounds of this invention, besides being effective coccidiostatsagainst various species, also control one or more of the "resistant"species.

The compounds of this invention have the following formula: ##STR3##wherein R' is alkyl having one to three carbon atoms; X⁻ is a nontoxicanion; b and c are positive numbers such that the positive charge of bmoles of cation are neutralized by c moles of anion X^(-;) and -N is abicyclic heterocycle base, of the group consisting of: ##STR4## whereinthe dotted line indicates that the alpha methyl group can be present ora hydrogen group can be present with the proviso that one and only onemethyl group is present.

As described more fully below, these anticoccidial compounds areprepared by reaction of 2-R'-4-amino-5-halomethyl-pyrimidine or2-R'-4-amino-5-alkoxymethyl pyrimidine with the bicyclic heterocyclicbase.

It will be apparent to one skilled in the art that other positionisomers and homologues of the above compounds can be easily prepared andpossess coccidiostatic activity. Specifically, in the bicyclic ringsystems described, there can be up to two methyl substituents, one ofwhich is alpha to the linking nitrogen and the other in any otheravailable position, so long as it is not in the other alpha position.Two illustrations of these compounds are, e.g.: ##STR5##

It will be apparent to one skilled in the art that the compounds of theabove structural formulas are all most easily synthesized, recovered,and employed as quaternary halide hydrohalide salts wherein the halidecan be chloride or bromide.

The preferred compounds of the invention are compounds in which thenitrogen-containing heterocyclic base is thieno[2,3-c]pyridine;thieno[3,2-c]pyridine; or furo[3,2-c]pyridine; respectively: ##STR6##The dotted line indicates that the methyl group can be in eitherposition, or neither, but not in both at the same time. Morespecifically,6-[(4-amino-2-ethyl-5-pyrimidinyl)-methyl]-7-methylthieno[2,3-c]pyridiniumchloride hydrochloride;6-[(4-amino-2-ethyl-5-pyrimidinyl)methyl]-2,7-dimethylthieno[2,3-c]pyridiniumchloride hydrochloride;6-[(4-amino-2-ethyl-5-pyrimidinyl)-methyl]-5-methylthieno-[2,3-c]pyridiniumbromide hydrobromide;5-[(4-amino-2-ethyl-5-pyrimidinyl)-methyl]-4-methylthieno[3,2-c]pyridiniumchloride hydrochloride;5-[(4-amino-2-isopropyl-5-pyrimidinyl)-methyl]-6-methylthieno[3,2-c]pyridiniumbromide hydrobromide;5-[(4-amino-2-ethyl-5-pyrimidinyl)-methyl]-4-methylfurano[3,2-c]pyridiniumbromide hydrobromide; and5-[(4-amino-2-ethyl-5-pyrimidinyl)-methyl]-6-methylfurano[3,2-c]pyridiniumchloride hydrochloride are among the most preferred compounds of theabove group.

The most preferred salt compounds are the chloride hydrochloride forms.The bromide hydrobromide salts are also preferred. In these preferredcompounds, X⁻ is bromide or chloride. The quaternary nontoxic anion canalso be any inorganic anion such as iodide or nitrate, sulfate,phosphate, and the like, or the anion of an organic acid such as citric,tartaric, acetic, stearic, succinic, benzoic, phthalic, phenoxyacetic,embonic, abietic, 2-naphthalene sulfonic acid, pamoic acid or1,5-naphthalene disulfonic acid. It may also be the anion of a polymersuch as a polyphosphate or polystyrene-sulfonate ion. The nature of thenontoxic anion is not critical and any anion may be employed as long asit is not unduly toxic for the poultry.

There are a number of processes which can be used to synthesize thegroup of compounds described in this application. Generally, theappropriately substituted pyrimidine (hereinafter called "thepyrimidine") and the methylated nitrogen-containing bicyclic(hereinafter called "the base"), are condensed by reacting the two in asolvent system. The starting materials, respectively the pyrimidine andthe base, are either known and described in the art or can be easilysynthesized using processes described in the art.

A. The Acid Ester Process

The preferred process utilizes the appropriate 5-hydroxymethylpyrimidine which has been converted to the ester of a strong acid in thereaction with the base. By the term, strong acid ester, we mean that theester at position 5 of the pyrimidine which is formed from thehydroxymethyl group and a strong inorganic acid such as a hydrohalicacid. For example, the 2-R'-4-amino-5-halomethyl pyrimidinedihydrohalide, in which the halogen is bromine or chlorine and R' is asdefined above, is reacted directly with the base.

An excess of the base or, alternatively, organic solvents inert underthe reaction conditions such as acetonitrile or an N,N-diloweralkylalkanoamide such as DMF may be employed as the reaction medium. Thereaction temperature is not critical and it is preferred to carry outthe process at about room temperature. After a short time, the product,which is usually the quaternary salt, crystallizes and is recovered byknown techniques such as filtration or centrifugation. This process maybe represented as follows: ##STR7## where R' is alkyl of 1 to 3 carbonatoms; X' is a halogen such as chlorine or bromine; X⁻, b, and c are asdefined above; and N is the bicyclic base as defined above.

Although the 5-halomethyl pyrimidines are generally most convenientlyemployed for reaction with the nitrogen-containing heterocyclic base,the quaternization may also be brought about with other esters of the2-R'-4-amino-5-hydroxymethyl pyrimidine. Suitable esters are those oforganic sulfinic and sulfonic acids such as the methylsulfinate orp-toluenesulfonate. The reaction can be conducted so that the particularsalt desired for treating coccidiosis is obtained directly.Alternatively, the quaternary salt recovered from the synthetic reactionmedium may be conveniently metathesized to another salt by techniquesknown in the art.

B. The Ether Cleavage Process

Another process utilizes 2-R'-4-amino-5-methylether pyrimidine inreaction with the base in the presence of an excess of hydrohalic acid,wherein the halogen is chlorine or bromine.

This process can be represented structurally as: ##STR8## wherein R' isalkyl of 1 to 3 carbon atoms; R² is an alkyl or aralkyl radical havingless than nine carbon atoms; X' is a halogen such as chlorine orbromine; and -N is as defined above.

The pyrimidine reactant employed (in Formula III above) is thehydrohalide salt of 2-R'-4-amino-5-hydrocarbonoxymethyl pyrimidine. Thehydrocarbon radical which forms part of the ether substituent at the5-position (R² of Formula III) may be an alkyl or an aralkyl radical,preferably a radical containing less than nine carbon atoms. Thus R² maybe a loweralkyl group such as methyl, ethyl, isopropyl, propyl, t-butyl,or amyl, or benzyl. Pyrimidines having a methoxymethyl orisopropoxymethyl are preferred. These compounds are generally known;those which have not been specifically disclosed are readily prepared bythe methods utilized for the known related compounds. For example, seeJ.A.C.S. 59, 1052 (1947) or U.S. Pat. Nos. 3,161,642 or 2,350,265.

The base employed is also in the form of the hydrohalide salt. Thesepyrimidinyl methylethers are reacted with the base, the latter asdefined above, under the following reaction conditions.

An excess of the base is employed over the pyrimidine. Satisfactoryresults are obtained when from 1.5 to 10 moles of base are used per moleof pyrimidine.

As will be noted from the above flow diagram, in our process, apyrimidylmethyl ether (III) is cleaved by the base hydrochloride withformation of the desired quaternary salt. Although the two reactants maybe mixed as hydrochloride salts and the reaction carried out asdescribed hereinbelow, it is also possible to charge the pyrimidine andthe base to the reaction mixture as free bases, and to form the salts insitu by addition of hydrogen chloride to the reaction mixture.

One feature of this process is that the cleavage of the2-loweralkyl-4-amino-5-hydrocarbonoxymethyl pyrimidine with the basehydrochloride is brought about in the presence of excess hydrogenhalide, i.e., an excess over the amount required to convert all of thepyrimidine and base present to the corresponding hydrohalides. We employa 7.5 to 100% excess of acid (over the amount required for saltformation).

The process is carried out at atmospheric pressure and at elevatedtemperatures of between about 110° C. and 200° C. It will be appreciatedthat the optimum reaction time is dependent to a large degree on thetemperature employed. Satisfactory results are obtained in as little as5 to 10 minutes at higher temperatures whereas 10 to 12 hours or longermay be required at the lower temperatures. When the process is conductedwithin the preferred temperature range, the quaternary salt is formed inhigh yield in from about 1 to 8 hours. The reaction mixture is aheterogenous one at several stages of the process so that the efficiencyof mixing may become a factor in large-size equipment, and the optimumreaction time will increase as stirring efficiency decreases.

This process is carried out in an organic solvent medium. A number ofaromatic and aliphatic solvents can be employed, representative examplesof which are toluene, xylene, secondary butyl benzene,tetrachloroethane, tetrachloroethylene and the chlorobenzenes. It isconvenient to use a solvent having a boiling point close to the desiredreaction temperature so that the process may be conducted under reflux.The solvent should, of course, have a boiling point of at least 110° C.in order to satisfy the temperature conditions discussed above. Inaddition, the solvent should be water-immiscible for the reason thatundesired reaction by-products such as lower alkanols and/or watershould be continuously removed from the reaction site in order toachieve optimum yields. Several methods or techniques are suitable forremoval of low-boiling byproducts, such as continuous distillation ofthe organic solvent and replacement thereof by fresh solvent,distillation or refluxing through a steam-cooled condenser which permitsescape of low-boiling material but returns the organic solvent to thereaction vessel, or use of commercially-available mechanical separators.

At the end of the reaction period, the product is conveniently recoveredby cooling the reaction medium and separating the substantially puresolid from the organic solvent. The product is freed of residualreaction solvent by washing with suitable solvents such as acetonitrile,isopropanol or ether. When this process is carried out under thepreviously described reaction conditions, the desired products areobtained in yields exceeding 80% and in many cases the yields willapproach 90% of theoretical.

C. Other Processes

Other modifications of the two above processes are possible.

For instance, either the 5-hydrocarbonoxymethyl pyrimidine or the5-hydrocarbonoxymethyl pyrimidine hydrohalide can be reacted with anexcess of the base hydrohalide in the absence of a solvent by refluxingat an elevated temperature, preferably between 130°-220° C., underpressure if necessary, for a period between 30 minutes and 10 hours. Thehydrohalides can be prepared in situ if desired by first placing thepyrimidine and the base in a low-boiling solvent and passing throughhydrohalide gas, evaporating the solvent at a temperature below 100° C.,and then heating to the reaction temperature. The product in either casecan be recovered by dissolving the reaction product mixture in a solventlike ethanol or propanol and then recrystallizing using the usualtechniques.

Another modification utilizes the reaction between the 5-hydroxymethylpyrimidine hydrohalide, preferably formed in situ by reaction of the5-hydroxymethyl-4-amino-2-R'-pyrimidine with the base hydrohalide in anorganic solvent such as benzene, toluene or xylene, at a pH of between 3and 6.5. Additional aqueous acid is added if necessary. The reaction iscarried out at elevated temperatures, such as between 160°-170° C. Thecrux of this modification is that the solvent system and water arepermitted to evaporate from the reaction mixture, the water is removedfrom the solvent, and the solvent recycled to prevent the ionization ofthe hydrohalic acid present with concomitant reduction of the corrosivenature of the system.

Other possible modifications of the process involve reacting a5-hydroxymethyl-4-amino-2-R'-pyrimidine with the base by adding firstthe 5-hydroxymethyl pyrimidine into a previously prepared reactionmedium comprising a mixture of thionylchloride and anN,N-dialkylformamide, then adding the base. The latter can either be thefree base or the base hydrohalide. The reactive medium is prepared fromstoichiometric quantities of the two components. This medium is kept atlow temperatures (from about -5° C. to 10° C.) while the pyrimidine isadded; then the mixture is heated and the base added. After addition ofthe latter, the reaction is kept at reflux for one to two hours,whereupon the mixture is cooled and the product recovered.

In addition, 5-(triloweralkylammonium)methyl-4-amino-2-R'-pyrimidinehalide, especially chloride, will metathesize with the base, as will5-(triloweralkylphosphonium)-methyl-4-amino-2-R'-pyrimidine halide,especially chloride. Another analogous method utilizes the reactionbetween the tetrachlorozinc complex of1-(2-R'-4-amino-pyrimidin-5-yl)methyl-base with ammonia.

Another modification is that the reaction of a5-halomethyl-4-amino-2-R'-pyrimidine with the base is conducted indimethylsulfoxide at a temperature between 40°-135° C. for 0.5 to 3.0hours, in the optional presence of an alkali metal halide salt, such aspotassium bromide, then an arylsulfonic acid such as p-toluene sulfonicacid is added to the reaction mixture whereupon the mixture is refluxedfor a few minutes, then cooled, and the product recovered. This processis obviously very similar to the acid ester process described above andcan also be considered a variation of that process.

In using the compounds of the invention in the treatment and preventionof coccidiosis, they are conveniently fed to poultry as a component ofthe feed of the animals although they may also be given dissolved orsuspended in the drinking water. According to one aspect of theinvention, novel compositions are provided in which compounds describedabove are present as an active anticoccidial ingredient. Suchcompositions comprise the compounds of the invention intimatelydispersed in or admixed with an inert carrier or diluent. By an inertcarrier is meant one that is nonreactive with respect to the compoundsof the invention and that may be administered with safety to theanimals. The carrier or diluent is preferably one that is or may be aningredient of the animal feed.

The novel compositions which are a preferred feature of the inventionare the so-called feed supplements in which the active anticoccidialcomponent is present in relatively large amounts and which are suitablefor addition to the poultry feed either directly or after anintermediate dilution or blending step. Examples of carriers or diluentssuitable for such feed supplement compositions are solid orallyingestible carriers such as distillers' dried grains, corn meal, citrusmeal, fermentation residues, ground oyster shells, Attapulgus clay,wheat shorts, molasses solubles, corn cob meal, edible vegetablesubstances, toasted dehulled soya flour, soybean mill feed, antibioticmycelia, soya grits, crushed limestone, and the like. The compounds ofthe invention are intimately dispersed or admixed throughout the solidinert carrier by methods such as grinding, stirring, milling ortumbling. By selecting proper diluents and by altering the ratio ofcarrier to active anticoccidial component, feed supplement compositionsof any desired concentration may be prepared. Formulations containingfrom about 1% to about 40% by weight, and preferably from about 2-25% byweight of active anticoccidial component are particularly suitable foraddition to poultry feeds, and feed supplement compositions containingfrom about 5-15% by weight of active anticoccidial component are verysatisfactory. The active anticoccidial component is normally dispersedor mixed uniformly in the diluent but in some instances may be sorbed onthe carrier. The optimal concentration of active anticoccidial component(coccidiostat) in these feed supplements will depend to some extent onthe particular compound employed. Since it is convenient for the feedmanufacturer to use about one pound of feed supplement for each ton offinished feed, the preferred concentration of any one of ourcoccidiostats in a feed supplement is partly a function of the level ofactive ingredient desired in the finished feed.

In addition to being employed alone in the feed mixes, the novelcompounds of this invention can be employed in combination with otherknown coccidiostats. In the latter case, full spectrum coccidiostaticactivity can be assured, even against resistant strains. Othercoccidiostats such as amprolium, ethopabate, nicarbazin, robenzidene,sulfaquinoxaline, pyrimethamine, alklomide, sulfanitran, clopidol,nitromide, zoalene, roxarsone, arsanilic acid, enquinolate,deconquinate, monensin, nitrophenide, furazolidone, nihydrazone,nitrofurazone, dimethyalium, and clothiamine, etc., among others, may beused in such combinations.

Examples of typical feed supplements containing a pyridinium quaternarysalt dispersed in a solid inert carrier are:

    ______________________________________                                                                  lbs.                                                ______________________________________                                        A.                                                                                 6-[(4-amino-2-ethyl-5-pyrimidinyl)-                                           methyl]-7-methylthieno[2,3-c]pyridinium                                       chloride hydrochloride      6.0                                               Wheat standard midlings    94.0                                          B.                                                                                 5-[(4-amino-2-ethyl-5-pyrimidinyl)-                                           methyl]-4-methylthieno[3,2-c]pyridinium                                       chloride hydrochloride     10.0                                               Corn distillers' dried grains                                                                            90.0                                          C.                                                                                 5-[(4-amino-2-ethyl-5-pyrimidinyl)-                                           methyl]-6-methylfurano[3,2-c]pyridinium                                       chloride hydrochloride     20.0                                               Corn germ meal             30.0                                               Corn distillers' grains    50.0                                          ______________________________________                                    

These and similar feed supplements are prepared by uniformly mixing theproduct with the carrier or carriers.

The feed supplements of the type illustrated hereinabove are usuallyfurther diluted with materials such as corn meal or soybean meal beforebeing incorporated in the animal feed. This dilution serves tofacilitate uniform distribution of the substance in the finished feed.The finished feed is one that contains a sources of fat, protein,carbohydrates, minerals, vitamins and other nutritional factors.

The amount of drug (anticoccidial compound) required for control ofcoccidiosis in poultry will, of course, vary somewhat with the specificcompound or compounds employed. The compounds of Formula I above areeffective in preventing the disease when administered at levels of lessthan about 0.05% by weight of the feed. With the preferred compounds ofthe invention, i.e., the6-[(4-amino-2-loweralkyl-5-pyrimidinyl)methyl]thieno[2,3-c]pyridinium or6-[(4-amino-2-loweralkyl-5-pyrimidinyl)methyl]-thieno-[3,2-c]pyridiniumsalts, good prophylactic results were obtained when from about 0.01% toabout 0.05% by weight of the total feed consumed is administered; formost satisfactory results it is preferred that the poultry feed containbetween about 0.001% and 0.025% by weight of the anticoccidial compound.When the anticoccidial compounds are to be employed as therapeuticagents, the higher levels are used for relatively short periods of time.Thus, concentrations of about 0.02%-0.05% by weight of the feed may beadvantageously administered in treating an established outbreak ofcoccidiosis. It is desirable to employ the lowest levels that affordfully adequate control of coccidiosis in order to eliminate as far aspossible any risk of side effects that might appear on prolonged feedingof the compounds.

Many of the compounds of the invention are desirably or advantageouslyadministered to poultry by way of the drinking water of the birds. Thismethod of treatment is often employed in the therapeutic use of ourcompounds since poultry with coccidiosis are apt to consume less solidfeed than normal birds. The water-soluble compounds may be addeddirectly to the drinking water. Alternatively, water-soluble powders maybe prepared, in which the coccidiostat is intimately admixed with asuitable carrier, such as dextrose or sucrose, and these powders addedto the drinking water of poultry as necessary. Such water-solublepowders may contain any desired concentration of coccidiostat, andpreparations containing from 1%-25% by weight of active component aresuitable.

EXAMPLE 16-[(4-Amino-2-ethyl-5-pyrimidinyl)methyl]-7-methylthieno-[2,3-c]pyridiniumchloride hydrochloride

17.8 G. of 4-amino-2-ethyl-5-pyrimidinylmethyl bromide hydrobromide and8.94 g. of 7-methylthieno[2,3-c]-pyridine are mixed in 50 ml. dryacetonitrile. The reaction mixture is stirred mechanically overnight atroom temperature. The colorless precipitate is collected and washed withether; after recrystallization from methanol-acetone, 16.5 g. (61.5%)are obtained, m.p. 249°-250° C., dec., identified as6-[(4-amino-2-ethyl-5-pyrimidinyl)-methyl]-7-methylthieno[2,3-c]pyridiniumbromide hydrobromide.

The bromide hydrobromide salt is dissolved in 50 ml. concentratedhydrochloric acid and precipitated with 1.5 liters of acetone. Thisprocess is carried out four times. A colorless crystalline solid isobtained, 7.85 g. (60%), m.p. 249°-250° C., dec., identified as6-[(4-amino-2-ethyl-5-pyrimidinyl)methyl]-7-methylthieno-[2,3-c]pyridiniumchloride hydrochloride.

The compounds,6-[(4-amino-2-ethyl-5-pyrimidinyl)-methyl]-5-methylthieno[2,3-c]pyridiniumchloride hydrochloride and6-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-thieno[2,3-c]pyridiniumchloride hydrochloride can be prepared following the above reaction,using the reactants 4-amino-2-ethyl-5-pyrimidinyl-methyl bromidehydrobromide with 5-methylthieno[2,3-c]pyridine or4-amino-2-methyl-5-pyrimidinyl-methyl bromide hydrobromide withthieno[2,3-c]-pyridine, respectively.

EXAMPLE 26-[(4-Amino-2-ethyl-5-pyrimidinyl)methyl]-2,7-dimethylthieno[2,3-c]pyridiniumbromide hydrobromide

891 Mg. of 2-ethyl-4-amino-5-bromomethyl pyrimidine hydrobromide isdissolved in 5 ml. of dimethylformamide (DMF), 1.95 g. of2,7-dimethylthieno[2,3-c]-pyridine is added; a precipitate formsimmediately. The precipitate is collected, washed with DMF, anddiscarded. The filtrates are stirred at room temperature overnight,diluted with ether, and the off-white precipitate collected and washedwith ether. The solid is dissolved in methanol, hydrogen bromide gasintroduced, and the colorless product isolated frommethanol-isopropanol. 270 Mg. of product,6-[(4-amino-2-ethyl-5-pyrimidinyl)methyl]-2,7-dimethylthieno[2,3-c]pyridiniumbromide hydrobromide is recovered, m.p. 215°-216° C., dec., 20% yield.

EXAMPLE 35-[(4-Amino-2-ethyl-5-pyrimidinyl)methyl]-4-methylthieno-[3,2-c]pyridiniumchloride hydrochloride

82.5 G. of 4-amino-2-ethyl-5-pyrimidinylmethyl bromide hydrobromide issuspended in 1000 ml. dry acetonitrile. 82.5 g. of4-methylthieno[3,2-c]pyridine is added and the reaction mixture isstirred over two days at room temperature. The colorless precipitate iscollected, washed with ether, and recrystallized frommethanol-isopropanol to give a colorless solid, 69.5 g., m.p.218.5°-220° C., dec. It is recrystallized again frommethanol-isopropanol; 52.1 g. (42%), m.p. 229°-230° C., des., andidentified as5-[(4-amino-2-ethyl-5-pyrimidinyl)-methyl]-4-methylthieno[3,2-c]pyridiniumbromide hydrobromide.

The bromide salt, above, is then dissolved in 130 ml. concentrated HCland precipitated with acetone. This procedure is carried out five times.The result is 33.0 g. (33%), m.p. 229°-230° C., dec., of5-[(4-amino-2-ethyl-5-pyrimidinyl)methyl]-4-methylthieno[3,2-c]-pyridiniumchloride hydrochloride.

The other compounds which are prepared according to this invention arelisted in Table I. The condensation process used is that describedabove, in Examples 1 to 3. In each case the 5-bromomethyl pyrimidine andthe base are condensed in an inert solvent in approximately equimolaramounts at ambient temperatures (about 25° C.). The reference to "basetype" in the Table is to the structures A, B, or C, each of which ismore fully discussed infra.

                                      TABLE I                                     __________________________________________________________________________    EXAMPLE TITLE OF COMPOUND   BASE TYPE                                                                            YIELD                                                                             MELTING POINT                          __________________________________________________________________________    4     6-[(4-amino-2-n-propyl-5-pyrimidinyl)-                                                              A      44% 269-270° C. Dec.                      methyl]-7-methylthieno[2,3-c]pyridinium                                       bromide hydrobromide                                                    5     5-[(4-amino-2-ethyl-5-pyrimidinyl)-                                                                 B      72% 270-271° C. Dec.                      methyl]-6-methylthieno[3,2-c]pyridinium                                       bromide HBr                                                             6     5-[(4-amino-2-ethyl-5-pyrimidinyl)-                                                                 B      67% 271-272° C. Dec.                      methyl]-thieno[3,2-c]pyridinium                                               bromide HBr                                                             7     5-[(4-amino-2-ethyl-5-pyrimidinyl)-                                                                 C      30% 228-230° C. Dec.                      methyl]-4-methylfuro[3,2-c]pyridinium                                         bromide hydrobromide                                                    __________________________________________________________________________

EXAMPLE 86-[(4-Amino-2-ethyl-5-pyrimidinyl)methyl]-7-methylthieno-[2,3-c]pyridiniumchloride hydrochloride

50 G. of 2-ethyl-4-amino-5-methoxymethyl pyrimidine, 50 g. of7-methylthieno[2,3-c]pyridine and 500 ml. of xylene are placed in a2-liter flask equipped with reflux condenser, stirrer, thermometer andgas inlet tube. Hydrogen chloride gas is added to this mixture over 30minutes at a rate sufficient to add an amount equivalent to 0.2 moles,that of the pyrimidine. The temperature rises to about 67° C. The gasinlet tube is replaced with a distillation unit and the mixture heatedat reflux (138° C.) for two hours during which fresh xylene is added toreplace the volume of liquid that distills. An additional 25 g. of7-methylthieno[2,3-c]pyridine are added and the mixture refluxed for 40minutes. At the end of the reflux period, the reaction mixture is cooledto 65° C., the xylene decanted, and 50 ml. of acetonitrile added to theresidue. The resulting mixture is stirred at room temperature for about12 hours, filtered, and the solid6-[(4-amino-2-ethyl-5-pyrimidinyl)methyl]-7-methylthieno-[2,3-c]pyridiniumchloride hydrochloride thus obtained washed. The product has a m.p. of249°-250° C., dec.

The above reaction is also carried out using chlorobenzene as thesolvent instead of xylene; and the second addition of7-methylthieno[2,3-c]pyridine is omitted. The same product,6-[(4-amino-2-ethyl-5-pyrimidinyl)methyl]-7-methylthieno[2,3-c]pyridiniumchloride hydrochloride is obtained.

EXAMPLE 96-[(4-Amino-2-ethyl-5-pyrimidinyl)methyl]-7-methylthieno-[2,3-c]pyridiniumpamoate monohydrate

To a mixture of6-[(4-amino-2-ethyl-5-pyrimidinyl)-methyl]-7-methylthieno[2,3-c]pyridiniumchloride hydrochloride (7.14 g., 0.02 mole) and pamoic acid disodiumsalt (8.64 g., 0.02 mole), there is added 100 ml. water. The reactionmixture is heated on the steam bath for five hours. The cooled mixtureis filtered and the precipitate is washed with acetone, then ether, andair dried to give the product as an analytically pure solid, 13.30 g.(96%).

Anal. calc'd for C₃₈ H₃₂ N₄ O₆ S·H₂ O: C, 66.07; H, 4.96; N, 8.11;found: C, 65.82; H, 5.32; N, 7.87.

EXAMPLE 106-[(4-Amino-3-ethyl-5-pyrimidinyl)methyl]-7-methylthieno-[2,3-c]pyridinium1,5-naphthalene disulfonate monohydrate

To a mixture of6-[(4-amino-2-ethyl-5-pyrimidinyl)methyl]-7-methylthieno[2,3-c]pyridiniumchloride hydrochloride (7.14 g., 0.02 mole) and1,5-naphthalenedisulfonic acid disodium salt (7.73 g., 0.021 mole),there is added 75 ml. water. The reaction mixture is heated on a steambath for two hours and then cooled to room temperature. The precipitateis collected by filtration, washed with some fresh water, then acetone,and finally air dried to give the product as a colorless, analyticallypure solid, 11.25 g. (95%).

Anal. calc'd for C₂₅ H₂₄ N₄ O₆ S₃ ·H₂ O: C, 50.83; H, 4.44; N, 9.48;found: C, 50.26; H, 4.47; N, 9.05.

Many other equivalent modifications of the invention would be apparentto those skilled in the art from a reading of the foregoing without adeparture from the inventive concept.

What is claimed is:
 1. A compound having the following formula: ##STR9##wherein R' is alkyl having 1 to 3 carbon atoms; X⁻ is a nontoxic anion;b and c are integers such that the positive charge of b moles of cationare neutralized by c moles of anion X^(-;) and -N is a member of thegroup consisting of: ##STR10## wherein the dotted line indicates thatthe alpha methyl group can be present or a hydrogen group can bepresent, with the proviso that one and only one methyl group is present.2. A compound according to claim 1 wherein the nontoxic anion is chloroor bromo.
 3. A compound according to claim 2 wherein R' is ethyl.
 4. Acompound according to claim 3 wherein -N is: ##STR11##
 5. A compoundaccording to claim 3 wherein -N is: ##STR12##
 6. A compound according toclaim 3 wherein -N is: ##STR13##
 7. A compound according to claim 1wherein R' is ethyl, X⁻ is chloro and -N is: ##STR14##
 8. A compoundaccording to claim 1 wherein R' is a-propyl, X⁻ is chloro and -N is:##STR15##
 9. A compound according to claim 1 having the followingformula: ##STR16## wherein R' is alkyl having 1 to 3 carbon atoms; X⁻ isa non-toxic anion; b and c are integers such that the positive charge ofb moles of cation are neutralized by c moles of anion X⁻.